Nature has newly reported that genetic variants may disrupt the production of myelin

Among Alzheimer's victims, 40 to 65 percent have a variant
of a gene called APOE4.
Scientists have long known that this variant significantly increases the risk of neurodegenerative diseases, especially when a person inherits a copy of APOE4 from both parents, but they are still learning the molecular mechanisms
that explain the role of APOE4.

One way APOE4 may contribute to Alzheimer's disease is by causing cholesterol to accumulate within oligodendrocytes, reducing the cell's ability to perform its main function: producing fatty myelin sheaths
that protect neurons and help them transmit signals, according to a study published Nov.
16 in the journal Nature.
The study further found that in mice carrying APOE4, clearing blocked cholesterol — the main component of myelin — and allowing the substance to cross cell membranes partially restored myelin production and improved cognitive performance, suggesting that this is a therapeutic target against Alzheimer's disease
.

"They showed that one of the things apolipoprotein E did was that it appeared to affect lipid metabolism in oligodendrocytes, which hadn't been described as much before," said David Holtzman, a neuroscientist at Washington University in St.
Louis who was not involved in the study
.
Others have shown that APOE4 can affect lipids and cholesterol in many different cell types, particularly microglia and astrocytes, Holtzman said, "but as far as I know, no one has really paid special attention to oligodendrocytes
.
" ”

"Many biological pathways are disturbed by APOE4," said
study co-author Li-Huei Tsai, a neuroscientist at MIT's Pikaul Institute for Learning and Memory.
Because the APOE gene encodes for a protein responsible for transporting lipids between cells, Tsai said, the researchers decided to focus on how this variant disrupts the metabolism of cholesterol and other lipids
.

Through transcriptome analysis, the researchers compared postmortem brain tissue from Alzheimer's patients with non-Alzheimer's disease patients and measured various gene expression levels in those with APOE4 variants with 0, 1 or 2 copies, and the results showed that "APOE4 has a huge impact on gene expression," Tsai said, especially for many genes
that affect lipids.
A similar analysis of oligodendrocytes found that genes related to making cholesterol were significantly upregulated in cells, while genes related to making myelin were down-regulated
, she said.

"What we see from gene expression data is counterintuitive," said Manolis Kellis, a computational biologist at MIT's Computer Science and Artificial Intelligence Laboratory and a co-author of the study, adding that the signals don't seem to match
because the genome is regulated in different directions.

To delve deeper into this mystery, the researchers performed lipid analysis
on brain tissue from people who carry at least one APOE4 or APOE3 gene.
APOE4 or APOE3 is the most common variant of the APOE gene and is not associated with
an increased risk of developing Alzheimer's.
The results showed higher levels of cholesterol esters in the brain of APOE4, which are insoluble cholesterol
known to accumulate inside cells, Tsai said.
When the researchers stained human and mouse brain tissue from APOE4 homozygous, they found that cholesterol droplets accumulated
within oligodendrocytes of both.
Meanwhile, cholesterol was more prevalent
outside the cell in samples containing APOE3.

Researchers began to suspect that the APOE4 variant was blocking the transport
of cholesterol through oligodendrocytes membranes.
Imagine oligodendrocytes working like myelin printers, the emerging hypothesis is that these cells have a lot of ink (cholesterol), but the ink is stuck in the cartridge,

To verify the relationship between APOE4 and reduced myelin production, the researchers conducted a variety of experiments
.
First, they induced pluripotent stem cells to form oligodendrocytes (precursors of oligodendrocytes), which were then co-cultured with lab-induced
neurons.
Typically, these co-cultured oligoglial cells begin to form myelin
within a few weeks, Tsai said.
The researchers noted this effect in APOE3 co-culture, "but in APOE4 co-culture, we saw a significant reduction .
.
.
Characteristics of the myelin essential protein, "This indicates less production of myelin
.
" Transmission electron microscopy of brain tissue also showed that mice carrying APOE4 had fewer neurons with myelinated axons, and that the neuronal sheaths with myelinated sheaths were thinner
than those with APOE3.

The team then tried using cyclodextrins (a drug known to reduce cholesterol accumulation in cells) in vitro and in APOE4 mice to reduce cholesterol accumulation and restore myelin production
.
After two weeks of treatment with APOE4 oligodendron glial-neuronal co-culture, the myelin sheath increased to a level
close to APOE3 co-culture.
The researchers injected mice subcutaneously with the drug twice a week for 8 weeks and then compared
their brain tissue to mice that did not receive APOE4 treatment.
In the treated mice, cholesterol accumulated within oligodendrocytes decreased, and the researchers observed increased levels of extracellular myelin alkaline protein, suggesting that the treatment improved cholesterol flow and myelination formation
.
Finally, the researchers gave the mice several cognitive tests, and "what we saw was, indeed, that it improved cognitive performance.
"

Holtzman said he would like to see others confirm the results, and he is not yet convinced that the findings are clinically relevant
to humans.
"There are many mechanisms for how APOE4 alters the risk of Alzheimer's disease," he said, "and I'm not sure if that's one of those important mechanisms
.
" It's really hard to judge
.
Changes in cholesterol and myelin have the potential to lead to the decline or degeneration associated with Alzheimer's disease, he said, "but we know that APOE has done a lot of other things that have a huge impact on the pathology of Alzheimer's disease that has nothing to do with
these findings.
" ”

While APOE4 is associated with an increased risk of developing Alzheimer's and a sharp decline in cognitive performance after the onset of symptoms, "these effects of APOE4 on Alzheimer's can only be seen in the presence of Alzheimer's pathology," particularly typical accumulation of amyloid plaques in the brain or tangles
of tau protein within neurons.
He added that it is not yet known that APOE4 affects myelin levels in adults without Alzheimer's disease, and to his knowledge, no one has investigated this possibility
.
Thus, in APOE4 mice without Alzheimer's disease, myelin reduction and cyclodextrin-mediated myelin and cognitive function recovery were found to be clinically relevant or not clinically relevant in humans, he said
.

Tsai explained via email that past fMRI studies have linked genetic variants to decreased white matter, which is mainly composed of
myelinated nerve axons.
She added that her and her colleagues' work highlights the need to study Alzheimer's risk mechanisms that may begin before disease and cognitive decline begin
.
"Our findings suggest earlier opportunities for therapeutic intervention
," she said.
I think that's what's interesting about
this study.
”

Tsai said her lab won't be involved in any potential clinical trials to explore whether cyclodextrins could help reduce symptoms
in Alzheimer's patients.
Instead, she and her colleagues will continue to study the mechanisms
behind the blocking effect of oligodendrocytes caused by genetic variation.
"The more we know about how [cholesterol] gets there, the more potential drug discovery targets will emerge
.
"